The broad purpose of the research in this proposal is to understand how microenvironments (secondary coordination spheres) about metal ions control function. A bio-inspired synthetic approach is utilized that incorporates principles of molecular architecture found in the active sites of metalloproteins. Multidentate ligands will be developed that create rigid organic structures around metal ions. These ligands place hydrogen bond (H-bond) donors or acceptors proximal to the metal centers, forming specific microenvironments. One distinguishing attribute of these systems is that site-specific modulations in structure can be readily accomplished, in order to evaluate correlations with reactivity. A focus of this research is consideration of dioxygen binding and activation by metal complexes - processes linked directly to the maintenance of human health and aging. Long-term goals include developing structure function relationships in metal-assisted oxidative catalysis. Metalloproteins perform functions not yet achieved in synthetic systems. Our hypothesis is that the lack of control of the secondary coordination sphere in synthetic compounds is a major obstacle to desire functions. Results from structural biology show that H-bonds within the secondary coordination spheres of metalloproteins are instrumental in regulating function. Therefore the function and dysfunction of health-related metalloproteins can be understood in the context of changes in their microenvironments. It is still unclear, even in biomolecules, how non-covalent interactions are able to influence metal-mediated processes. Investigations into these effects require basic reactivity and mechanistic studies in which the effects of single components can be analyzed individually. We have developed synthetic H-bonding systems whereby control of the molecular components that define the structure around the metal ion is obtained;in turn, this permits the formation of systems whose activity can be tailored to a particular function. This ability to regulate the microenvironment allows for systematic studies into structure-function relationships that lead to fundamental understanding of chemical processes. Ultimately, this research will provide insights into the properties of biological catalysts and lead to new classes of synthetic catalysts that incorporate the exquisite control of reactivity characteristic of metalloenzymes.